Spinocerebellar Ataxia Type

Pathogenesis and Pathophysiology. SCA2 is an autosomal dominant hereditary disorder. Genetic analysis of a large Cuban founder population led to the mapping of the SCA2 locus on chromosome 12q.y Recently, a protein containing a polyglutamine expansion was detected in the brain of an SCA2 patient, suggesting that SCA2 is caused by a CAG repeat expansion.^ Subsequent molecular studies confirmed that SCA2 is caused by a CAG repeat mutation, with expanded alleles ranging from 35 to 39 repeats.

Neuropathological examinations of SCA2 patients have consistently revealed OPCA, characterized by a marked reduction in Purkinje cells and degeneration of the inferior olives, pontine nuclei, and pontocerebellar fibers. In most cases, additional degeneration of the posterior columns and

spinocerebellar pathways is evident, as well as cell loss in the substantia nigra. y

Epidemiology and Risk Factors. The incidence and prevalence of SCA2 are unknown. There are large regional variations due to founder effects. Large SCA2 families have been found in Cuba, Tunisia, Martinique, Austria, Germany, and Italy. SCA2 is a genetically determined disorder with no known environmental risk or precipitation factors. Children from SCA2 patients have a 50 percent risk of developing the disease.

Clinical Features and Associated Disorders. SCA2 can begin at any time from early childhood to late adulthood with features of anticipation. On average, the disease starts around the age of 35 years. All SCA2 patients suffer from a progressive cerebellar syndrome marked by ataxia of gait and stance, ataxia of limb movements, and dysarthria. Saccade slowing is a highly characteristic feature that is observed in the majority of SCA2 patients. About half the patients have vertical or horizontal gaze palsy. Cerebellar oculomotor abnormalities are rarely found in SCA2 patients. Typically, tendon reflexes are absent or decreased. Pyramidal tract signs are present in less than 20 percent of the patients. Vibration sense is decreased in most patients, but sensation is otherwise normal. Dementia, basal ganglia symptoms, pale optic discs, and bladder dysfunction are usually absent. y , y , y

Differential Diagnosis and Evaluation. Diagnosis of SCA2 is made by the demonstration of the CAG repeat expansion at the SCA2 locus. Clinically, SCA2 cannot be distinguished with certainty from other forms of ADCA-I. However, the presence of slow saccades, axonal neuropathy, and severe OPCA on MRI is suggestive of SCA2.

Evaluation. Nerve conduction findings are similar to those seen in SCA1 with low-amplitude SNAPs and normal or slightly reduced NCVs. In contrast to SCA1, MEPs in response to transcranial magnetic stimulation and VEPs are usually normal in SCA2. BAEPs are abnormal in less than half of SCA2 patients. SEPs after tibial nerve stimulation are usually abnormal. MRI shows diffuse cerebellar atrophy with marked brain stem atrophy, suggesting the presence of OPCA. In addition, the cervical spinal cord is atrophic in most patients( .Fig 35-2 ). y

Management. At present, there is no specific treatment for SCA2. Principles of symptomatic and palliative therapy are identical to those described for SCA1.

Prognosis and Future Perspectives. SCA2 is a progressive disorder. On average, these patients become wheelchair-bound about 15 years after disease onset. Median survival after disease onset is approximately 25 years. Patients in whom the disease begins in childhood appear to have a worse prognosis. Future studies must explore the mechanisms by which the SCA2 mutation leads to the regional specific pattern.

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